The Amazing Gleason Score

BY MARK SCHOLZ, MD


Everyone is excited about the latest craze in medical technology—genetic analysis of tumor cells, which I’ll call GAT for short. The scientific progress that has been made with GAT in my opinion is the second most exciting area of advancement in medical technology today (see further below for more about the first most exciting area). GAT technology is already being commercialized for use in the medical marketplace in products like Prolaris and Oncotype. This technology is able to predict the aggressiveness of prostate cancers, enabling us to differentiate between the men who need immediate treatment and those who can postpone treatment safely.

The predictive power of GAT is certainly exciting, but there is already an effective form of genetic testing available that has been around for more than 40 years, the Gleason scoring system. The Gleason system relies on the visual appearance of cells under the microscope to draw conclusions about their inner genetic makeup. In the medical world, using the visual appearance of the cancer cells is called phenotypic analysis. GAT is genotypic analysis.  Drawing conclusions about underlying genetic makeup by simple visual assessment is a pervasive in human experience.  In courtship, we rely on phenotypic analysis of the underlying genetic make-up of potential spouses to form an opinion about their suitability as potential mates.  Perusal of the genetic pool of immediate family members provides further insight.

So how can Gleason score draw conclusions about the underlying genetic potential for tumor aggressiveness simply by looking at the appearance of cells under a microscope?  The answer is to do a comparison of the visual appearance of cancer cells with the appearance of normal prostate cells. Normal cells in the prostate perform varied functions but still work together as a team.  Specifically, healthy cells form into definable structures called glands.  In these glands some cells manufacture prostatic fluid, a complex liquid comprising the ejaculate for the sperm to swim in.  Other cells organize to form ducts, a piping system to drain the fluid from the outer periphery of the gland and channel it into the middle of the prostate so that a large quantity of fluid can be expelled through the urethra at just the right moment.  All of these different cells work as a team and coexist in the prostate functioning together in a structured glandular arrangement.   
 
When a trained pathologist looks at tumor cells under the microscope he grades them by the degree of cellular disorder.  He is asking himself the question, “How much do these cells retain the normal glandular characteristics of the prostate gland?”  If a cross section of the tumor looks like an unbroken sheet of uniform cells, the cancer is high-grade; the cells have lost their ability to cooperate with each other and form glands. The cancer cells have been honed down into little race cars with only one mission, to aggressively pursue its own replicative destiny. When tumors have this appearance they are graded as a Gleason 9 or 10.  On the other hand, if the appearance of the tumor shows residual glandular components, it is less aggressive, perhaps a Gleason 7.  Gleason 6 “cancer,” the type the one that never spreads, looks almost like normal prostate gland tissue.  
 
Predicting future tumor behavior is obviously very important. How fast will it grow?  Is it likely to spread? How well can it be expected to respond to treatment?  As a result of decades of experience, doctors have learned to use the Gleason scoring system to accurately predict the long-term outcome in individual patients. The new GAT tests represent an important additional refinement, further enhancing our ability to predict the future behavior of an individual cancer. GAT holds one even bigger promise.  In the future we believe GAT testing will be a powerful aid in the selection of targeted therapy, i.e., picking cancer treatments with anticancer activity tailored to individual tumor types.  This hope, however, will have to be postponed until our limited armamentarium of effective treatments is further expanded.    
 
Now, what is it that I consider to be the most exciting area of medical progress? Since I am an impatient type of guy, someone who is looking for quick results, I find immunotherapy more exciting than GAT. To fully exploit the potential of GAT we will need to invent new pills for each of the myriad of genetically different tumor types. Immunotherapy on the other hand comes with its own “built-in” GAT system that enables it to target the unique genetic signature of individual cancer cells. The immune system is so smart, all we have to do is “flip the switch on” and starts cranking out genetically targeted anticancer therapy. Recent developments in the field of immunology are truly mind-boggling and hold promise for a big revolution in cancer therapy within the next 5-10 years.  I’ll try to address some of these recent advances in an upcoming blog. 

The Power of a Word

BY MARK SCHOLZ, MD

At an Active Surveillance Consensus Conference in 2007, it was openly bemoaned that the word “cancer” profoundly overstates the significance of low risk prostate cancer.  The pathology experts who were present, however, shot down the idea of a name change saying, “Under the microscope it looks like a cancer, so it’s cancer.” At that time no one had a rebuttal, so the subject was dropped. Now studies confirm that Gleason grade six prostate cancer never metastasizes.

In retrospect, I wish the conference attendees had been able to rise up to the name-change challenge. Back when the makers of 7-Up wanted to emphasize the distinctness of their product compared to other soft drinks, they came up with the name “Un-Cola,” a stroke of marketing genius. Since the pathology experts insist that low-risk disease is a cancer—we should undo the negativity of this word by renaming it: “The Un-Cancer.” Alternatively, the SHADES of Blue classification system calls this harmless type of prostate cancer SKY BLUE.

Misinterpreting the significance of the word cancer leads everyone to think, “I had better be safe and remove the gland.”  The biggest challenge of educating people about prostate cancer is overcoming their preconceived notions, what they already think they know about cancer.  Random biopsies are detecting cancers that are so small that even if they grow while under observation, they will still be curable.  And for the minority of men on active surveillance who develop progressive disease, at least they have real proof that their cancer truly needs intervention, for this minority, it’s not a paper tiger and undergoing treatment is justified.

Defining the Un-Cancer—The Basic Components of SKY

	Favorable	Ambiguous Zone	Unfavorable
Color Doppler or Multiparametric-MRI	< 10 mm  in maximum tumor dimension	11-17 mm  maximum tumor dimension	> 18 mm max tumor dimension
Highest Gleason Grade	Grade 3 + 3 = 6	3 + 4 = 7	4 + 3 = 7 or higher
PSA Density	Under 0.13	0.14 to 0.17	Over 0.18

Further In-depth Testing for SKY
New technology is also providing new insight into how favorable cancer can be distinguished from unfavorable cancer. The biggest advance is better imaging of the prostate. Other new blood and genetic tests such as Prolaris, Oncotype, MDx, OPKO 4K and Mitomics, can also ferret out the cancers that are prone to behave more aggressively or have been missed on the initial random biopsy.

The Drawbacks for Active Surveillance
The main concern is that the initial random biopsy missed a higher grade tumor somewhere else in the prostate. Most centers address this problem by doing random biopsies over and over. Repeated random biopsies are unpleasant and they can cause serious infections.  Multiple biopsies have also been associated with higher impotence rates and worse urinary symptoms. A better way is to rely on modern imaging with color Doppler ultrasound or multiparametric MRI (MP-MRI). Also, because with active surveillance prostate gland is left intact, there is the possibility of a new, higher grade cancer developing. The privilege of keeping the prostate intact entails the responsibility of close monitoring. Then, if a new higher grade cancer subsequently develops, it can be detected and treated at an early stage.

Anxiety and uncertainty about living with untreated cancer is also a problem, one that is often magnified by the treating physicians, surgeons or radiation doctors who often send an ambivalent and lukewarm message about active surveillance to their patients.  This half-hearted attitude is probably rooted in the doctor’s own uncertainties about untreated cancer. Despite all these very real issues, however, studies show that men on an active surveillance program are no more anxious than men who have had surgery or radiation and are being monitored after therapy to make sure their cancer stays in remission.

It’s Hard to Teach an Old Dog New Tricks
It’s easier to teach a proper golf swing to a true beginner than to someone who has previously developed bad habits.  The mind of a child learns a new language much more easily than the cluttered mind of the adult.  Good first impressions are valued so highly because we all know how hard it is to undo a bad first impression.  Changing the mindset of doctors and patients about how to treat something called CANCER is going to be a slow process.

Men need to realize that survival rates with low-risk prostate cancer managed with observation are extremely favorable.  Studies show that survival with active surveillance matches the survival of men getting immediate surgery. Men need to guard themselves from being rushed into unnecessary treatments that have irreversible side effects.

Active Surveillance: Knowing the Players, Betting the Odds

BY RALPH BLUM

Prostate cancer screening has led to the diagnosis and treatment of many cancers that would not have become life threatening during a man’s lifetime. Since Mark and I published our book, Invasion of the Prostate Snatchers, stressing the over-treatment of prostate cancer, the ascent of Active Surveillance has become the most game-changing factor in the management of this disease. And yet with the popularity of robotic surgery both doctors and patients are still opting for cutting out prostate with low-grade cancer unnecessarily.

Johns Hopkins was way ahead of the curve with their Active Surveillance program. In 2011, Hopkins published the results of a study involving 769 patients with low-risk prostate cancer who had been deemed eligible for the program. After seven years, only about 50 percent of the men had been treated with surgery or radiation. This meant some 385 men got a pass on one or another of life’s more risky and unpleasant procedures. Furthermore, it must be noted that not a single patient enrolled in the Hopkins’ Active Surveillance program died of prostate cancer.

The best prostate surgeons operate on an extremely small percentage of men over the age of 70, even though they meet the criteria for low risk disease. In fact, Hopkins only intervenes surgically in about 1 percent of those men. On the other hand, nationally, more like 80 percent are undergoing surgery or radiation. More than 90 percent of men over 65 with low to intermediate risk disease undergo treatment even though it is unlikely to extend their lifespan.

Active Surveillance reduces this radical over-treatment of low-risk, indolent cancers while allowing for curative intervention if and when the cancer progresses. Yet despite the obvious virtues of Active Surveillance, the dominant view in prostate care is that everyone who gets diagnosed gets treated in a one-size-fits-all approach regardless of their age, or the grade and stage of their cancer. Which means prostates are continuing to come out at a record pace, even though there is no benefit from the procedure. Senior urologists at top academic medical centers blame a host of reasons, not the least being the pressures on for-profit private hospitals to boost the volume of procedures in order to maintain their annual profit margins. Unfortunately, there are always financial issues involved.

While evidence is mounting that for men with low-risk disease Active Surveillance is both sensible and safe, the challenge is to further refine the protocols for separating out low-risk men from the men facing uncommonly aggressive tumors. In this regard there are some new genetic tests called Prolaris and Oncotype that help detect prostate cancer’s bad actors.

Meanwhile, if your prostate cancer has been diagnosed as low-risk (which has been defined as a Gleason Grade less than 7, a PSA less than 10), and your doctor is recommending immediate radical treatment, my advice to you is to get a second opinion from a doctor who has experience in treating patients with an Active Surveillance protocol. And if the time comes when you do trade Active Surveillance for surgery, never—repeat never—hesitate to ask the surgeon you are considering employing how many radical prostaectomies he performed this year. And last year. And the year before. I have been astonished to learn that hundreds of well-regarded urologists have performed fewer than ten a year. Last time I heard, between 150 and 200 procedures qualified you as “expert.” At that pace, you’d need to be a medically trained vampire to qualify. As for robotic surgery, it makes no great difference: I still want you closing in on 200 procedures, of whatever kind, before you get access to the prostate of any of my friends!